Modulator Of Activity Research Articles

Mitigating Winner-Take-All Resource Competition through Antithetic Control Mechanism.

Competition among genes for limited transcriptional and translational resources impairs the functionality and modularity of synthetic gene circuits. Traditional control mechanisms, such as feedforward and negative feedback loops, have been proposed to alleviate these challenges, but they often focus on individual modules or inadvertently increase the burden on the system. In this study, we introduce three novel multimodule control strategies─local regulation, global regulation, and negatively competitive regulation (NCR)─that employ an antithetic regulatory mechanism to mitigate resource competition. Our systematic analysis reveals that while all three control mechanisms can alleviate resource competition to some extent, the NCR controller consistently outperforms both the global and local controllers. This superior performance stems from the unique architecture of the NCR controller, which is independent of specific parameter choices. Notably, the NCR controller not only facilitates the activation of less active modules through cross-activation mechanisms but also effectively utilizes the resource consumption within the controller itself. These findings emphasize the critical role of carefully designing the topology of multimodule controllers to ensure robust performance.

How does group availability affect distributional equity of outdoor physical activity facilities? Evidence from Nanjing, China

ABSTRACT Most studies have measured the distributional equity of outdoor physical activity facilities (OPAFs) considering the unified accessible quantity and ignored the disparity of group availability. This study adopts a multidimensional approach to measure the distributional equity of OPAFs from the levels of city and residential units. Considering the old city of Nanjing as a sample, we first categorised the existing OPAFs into equipped sites, multifunctional sites, and trails and quantified the size and composition of three age groups in each residential unit. Second, we modularised OPAFs’ services through which each service type corresponds to one physical activity (PA) module and identified each module’s available groups. Third, we adopted accessibility, diversity, and supply-demand structure consistency (SDSC) to measure the distributional equity of OPAFs at two levels. The results showed that at the city level, the gap in the diversity of the modules between Group C (60 years old and above) and Groups A (15–59 years old) and B (60 years old and above) was more significant than that of accessible quantity, while the mean SDSC for Group C was much higher than those for Groups A and B. At the unit level, the differences in OPAFs’ group availability generated more significant differences in distributing diversity and SDSC than in the distribution of accessibility. Compared to traditional assessments, this tool integrates the disparity of OPAFs’ availability among different groups into the equity measurement, which can enhance the analytical precision and granularity and provide tailored OPAF optimisation strategies.

A Competition-Based Strategy for the Isolation of an Anti-Idiotypic Blocking Module and Fine-Tuning for Conditional Activation of a Therapeutic Antibody.

The masking of therapeutic antibodies by the installation of a blocking module that can be removed under certain physiological conditions, is becoming increasingly important to improve their safety and toxicity profile. To gain access to such masking units, we used chicken immunization in combination with yeast surface display and a competition-based FACS screening campaign to obtain anti-idiotypic single-chain Fv (scFv) fragments. This approach promotes the identification of functional masking units, since specificity and high affinity do not necessarily guarantee a paratope blocking effect. This strategy was used to isolate a scFv masking unit for the therapeutic antibody 6G11 (BI-1206), which is currently in clinical trials for the treatment of B-cell lymphoma to block the inhibitory Fcγ receptor IIB (CD32b). N-terminal fusion of the anti-idiotypic scFv to the 6G11 light chain successfully abolished binding to FcγRIIB in vitro. For conditional activation, a cleavable linker for the tumor-associated protease MMP-9 was implemented. To improve demasking efficiency, the affinity of the scFv mask was attenuated through rational design. The substitution of one key amino acid in the masking scFv reduced the affinity toward the 6G11 paratope by factor 10 but still mediated 9800-fold blocking of receptor binding. Proteolytic demasking allowed full recovery of therapeutic antibody function in vitro, supporting the concept of conditional antibody activation using this anti-idiotypic binding module.

Enhancing power quality in wireless DC power supplies through active power filtering: A computer simulation approach

This paper presents a computer simulation model for a high-power factor wireless DC power supply system, integrating an active power filter (APF) at the rectifier stage on the transmitter side using a rectifier boost technique. The APF, employing a MOSFET switch regulated by active pulse width modulation (APWM) within a current control loop, addresses pulsating and distorted AC supply currents caused by non-linear loads. A robust closed-loop control mechanism, including a subtractor circuit, proportional-integral (PI) controller, and comparator, ensures the generation of a continuous sinusoidal waveform synchronized with the supply voltage. The model utilizes a high-frequency inverter to convert DC to AC, which is then wirelessly transmitted via wireless power transfer (WPT) technology and converted back to DC by a high-frequency rectifier. MATLAB/Simulink simulation results show a significant reduction in total harmonic distortion (THD) of the AC supply current, complying with IEEE 519 standards. Selected results are presented to verify the proposed method's effectiveness in reducing harmonic distortions and enhancing power quality. This study highlights the advantages of WPT in scenarios where traditional wired connections are impractical and underscores the potential of this system for real-world applications, particularly in developing high-power factor wireless DC power supply systems.

Optimal drag-based collision avoidance: Balancing miss distance and orbital decay

The increasing number of objects in Low Earth Orbit makes active collision avoidance imperative for satellites operating in this region. For satellites non equipped with propulsion systems, the collision risk can be mitigated by exploiting the active modulation of aerodynamic forces through the ballistic coefficient. This article proposes a novel and high-fidelity optimal control approach for collision avoidance via aerodynamic drag modulation for an unpropelled SmallSat. Central to this approach is a cost function that jointly maximizes the miss distance while minimizing orbital decay during the maneuver. Moreover, the proposed approach has been rigorously tested through its application to the real-world scenario of the SOURCE satellite, slated for launch in 2025. For the satellite under investigation and a maneuver altitude of 350km, an in-track separation distance of around 22km can be accomplished within a warning time of 24h, which is large enough to conclude that the collision was successfully avoided. As a downside, however, this results in an additional loss in the semi-major axis of 165m and thus a reduced lifetime of the satellite. This balance between separation distance and additional loss in altitude can be flexibly adjusted by the user, which is demonstrated extensively in the article by means of a parameter study. Compared to the widespread use of chemical propulsion systems, this strategy naturally demands longer warning times due to the significantly lower available forces, and also radial offsets to the potential collision object cannot be in this case. Nevertheless, it offers a very promising alternative for active collision avoidance, especially for low-altitude applications.

Modulated ultrasound speakers – A common framework for analyzing air pump speakers

In this article we describe a new approach to sound generation based on active modulation of ultrasound. Active modulation of ultrasound provides an alternative to dynamic drivers and enables to reduce the size and volume of speakers. This feat in apparent contradiction to basic acoustics. In the article we provide for the first time an explanation of the underlying physics of modulated ultrasound speakers using a holistic lumped element model. Using the model, we explore different archiectures and highlight an archicture providing maximal sound pressure level for a given membrane area and displacement. Devices implementing the architecture were fabricated using MEMS technology. The sound pressure level response of the fabricated devices is compared to simulations highlighting the unique properties of the modulated ultrasound speakers.

Phage-induced disturbance of a marine sponge microbiome

BackgroundBacteriophages are known modulators of community composition and activity in environmental and host-associated microbiomes. However, the impact single phages have on bacterial community dynamics under viral predation, the extent and duration of their effect, are not completely understood. In this study, we combine morphological and genomic characterization of a novel marine phage, isolated from the Baltic sponge Halichondria panicea, and report on first attempts of controlled phage-manipulation of natural sponge-associated microbiomes.ResultsWe used culture-based and culture-independent (16S rRNA gene amplicon sequencing) methods to investigate bacterial community composition and dynamics in sponge microbiomes with and without the addition of phages. Upon application of a novel Maribacter specialist phage Panino under controlled conditions, we were able to detect community-wide shifts in the microbiome composition and load after 72 h. While bacterial community composition became more dissimilar over time in the presence of phages, species evenness and richness were maintained. Upon phage exposure, we observed the loss of several low-abundance constituent taxa of the resident microbiota, while other originally underrepresented taxa increased. Virulent phages likely induce community-wide disturbances, evident in changes in the total sponge microbial profile by specific elimination of constituent taxa, which leads to an increase in bacterial abundance of opportunistic taxa, such as the genera Vibrio, Pseudoalteromonas, and Photobacterium.ConclusionsOur findings suggest that sponge microbiome diversity and, by extension, its resilience depend on the maintenance of resident bacterial community members, irrespective of their abundance. Phage-induced disturbances can significantly alter community structure by promoting the growth of opportunistic bacteria like Vibrio and shifting the microbiome to a dysbiotic state. These insights highlight the role of bacteriophages in shaping microbiome dynamics and underscore the potential for phage application in managing bacterial community composition in marine host-associated environments.

Androgen receptor signalling in non-prostatic malignancies: challenges and opportunities.

The androgen receptor (AR) signalling pathway has been intensively studied in the context of prostate cancer, where androgen deprivation therapy is part of the standard of care for metastatic disease. By contrast, fewer studies have investigated the impact and translational potential of targeting AR in other cancer types where it is also expressed and functional. In this Review, we discuss the current understanding of AR in non-prostatic cancer types and summarize ongoing AR-directed clinical trials. While different androgen levels contribute to sexual dimorphism in cancer, targeting the AR system could benefit both sexes and help overcome resistance to targeted therapies. However, a bimodal function of AR signalling, which suppresses stromal changes associated with the early stages of cancer development, also needs to be considered. Future research is necessary to scrutinize cellular and molecular mechanisms of action of AR in cancer cells and the tumour microenvironment, to develop selective modulators of AR activity, and to identify patients with non-prostatic cancer who might benefit from targeting this pathway. AR-directed manipulation of host immune cells may offer a promising therapeutic approach for many types of cancers.

Succinate dehydrogenase mediated ROS production contributes to ASIC1a-induced chondrocyte pyroptosis in rheumatoid arthritis

Our previous study showed that acidic stimuli activate acid-sensitive ion channel 1a (ASIC1a), resulting in chondrocyte destruction associated with rheumatoid arthritis (RA). However, the exact underlying processes remain unclear. Recent evidence suggests that the production of reactive oxygen species (ROS) mediated by succinate dehydrogenase (SDH), contributes to chondrocyte damage. The objective of this study was to investigate the involvement of SDH in ASIC1a-induced chondrocyte destruction in RA and to explore the associated mechanisms both in vivo and in vitro. Our findings revealed that the cartilage of mice with collagen-induced arthritis (CIA) and acid-treated chondrocytes exhibited a substantial increase in SDH expression. Furthermore, SDH inhibition attenuates acidosis-induced pyroptosis in chondrocytes. Notably, ASIC1a activation through acid stimuli increases SDH activity and pyroptosis through the Ca2+/CaMKK2/AMPK pathway in chondrocytes. Mechanistically, SDH assembly factor 2 (SDHAF2) was identified as a key modulator of SDH activity induced by ASIC1a in acid-stressed chondrocytes. Moreover, the expression of SDH in CIA mouse chondrocytes decreased and the histological characteristics of ankle joint damage were reduced by the ASIC1a-particular blocker PcTx-1. Overall, these observations suggest that ASIC1a activation under acidic conditions increases SDH activity and modulates SDHAF2, thereby promoting chondrocyte pyroptosis through the Ca2+/CaMKK2/AMPK pathway.

Research and Design of an Active Light Source System for UAVs Based on Light Intensity Matching Model

The saliency feature is a key factor in achieving vision-based tracking for multi-UAV control. However, due to the complex and variable environments encountered during multi-UAV operations—such as changes in lighting conditions and scale variations—the UAV’s visual features may degrade, especially under high-speed movement, ultimately resulting in failure of the vision tracking task and reducing the stability and robustness of swarm flight. Therefore, this paper proposes an adaptive active light source system based on light intensity matching to address the issue of visual feature loss caused by environmental light intensity and scale variations in multi-UAV collaborative navigation. The system consists of three components: an environment sensing and control module, a variable active light source module, and a light source power module. This paper first designs the overall framework of the active light source system, detailing the functions of each module and their collaborative working principles. Furthermore, optimization experiments are conducted on the variable active light source module. By comparing the recognition effects of the variable active light source module under different parameters, the best configuration is selected. In addition, to improve the robustness of the active light source system under different lighting conditions, this paper also constructs a light source color matching model based on light intensity matching. By collecting and comparing visible light images of different color light sources under various intensities and constructing the light intensity matching model using the comprehensive peak signal-to-noise ratio parameter, the model is optimized to ensure the best vision tracking performance under different lighting conditions. Finally, to validate the effectiveness of the proposed active light source system, quantitative and qualitative recognition comparison experiments were conducted in eight different scenarios with UAVs equipped with active light sources. The experimental results show that the UAV equipped with an active light source has improved the recall of yoloV7 and RT-DETR recognition algorithms by 30% and 29.6%, the mAP50 by 21% and 19.5%, and the recognition accuracy by 13.1% and 13.6, respectively. Qualitative experiments also demonstrated that the active light source effectively improved the recognition success rate under low lighting conditions. Extensive qualitative and quantitative experiments confirm that the UAV active light source system based on light intensity matching proposed in this paper effectively enhances the effectiveness and robustness of vision-based tracking for multi-UAVs, particularly in complex and variable environments. This research provides an efficient and computationally effective solution for vision-based multi-UAV systems, further enhancing the visual tracking capabilities of multi-UAVs under complex conditions.

Nonlinear chiroptical response in lithium niobate metasurface driven by quasi-bound states in the continuum

Quasi-bound states in the continuum (QBIC) can significantly localize the light field and enhance light–matter interactions at the nanoscale, providing a platform for high-Q chiral light response and promoting nonlinear effects of materials. In this work, we numerically study the chiral linear and nonlinear light responses of the QBIC lithium niobate (LN) metasurface and achieve chirality modulation. The designed metasurface consists of LN nanobar dimers, and the chiral QBIC mode is excited by breaking the in-plane and out-of-plane symmetries of the structure, with the circular dichroism (CD) value and Q-factor reaching 0.92 and 1.24×104, respectively. Then, we investigate the second harmonic generation (SHG) of this device. The conversion efficiency of SHG under right circularly polarized pumping reaches 7.3×10−3, which is more than three orders of magnitude higher than that under the left circularly polarized pumping. The corresponding CD value of SHG reaches 0.99. In addition, by introducing phase change materials, we study the active modulation of the chiroptical response. Our results provide a crucial route for high-quality chiral light sources.

Discovery of new AMR drugs targeting modulators of antimicrobial activity using in vivo silkworm screening systems.

Global concerns about drug-resistant bacteria have underscored the need for new antimicrobial drugs. Emerging strategies in drug discovery include considering the third factors that influence drug activity. These factors include host-derived elements, adjuvants, and drug combinations, which are crucial in regulating antimicrobial efficacy. Traditional in vivo assessments have relied on animal models to study drug absorption, distribution, metabolism, excretion, and toxicity (ADMET). Alternative models, such as silkworms, are being explored to overcome the ethical and financial barriers associated with mammalian models. The silkworm has been proven effective in evaluating ADMET and in highlighting the therapeutic potential enhanced by third factors. Host factors (either mammalian or non-mammalian) enhance the antimicrobial activity of antimicrobial agents such as lysocin E. Additionally, using D-cycloserine to potentiate vancomycin has successfully combated vancomycin-resistant infections in silkworms. Leveraging silkworms in drug discovery could establish a novel screening method incorporating interactions with third factors, whether host related or non-host-related, thus promising new pathways for identifying antimicrobial drugs with unique mechanisms of action.

Near-perfect replication on amorphous alloys through active force modulation based on machine learning/neural network parameter prediction

Near-perfect replication on amorphous alloys through active force modulation based on machine learning/neural network parameter prediction

Innovative active terahertz modulator based on dynamic graphene-silicon arrays

This paper presents an innovative active terahertz (THz) modulator that utilizes dynamic graphene-silicon arrays (DGSAs) to overcome the challenges of dynamically manipulating THz waves. The DGSA combines the exceptional electrical properties of graphene with the enhanced optical absorption capabilities of silicon arrays, enabling dual-mode active control through optical pumping and electrical biasing. An 808 nm laser is used to photoexcite carriers in the silicon arrays for optical pumping while a bias voltage modulates the Fermi level of graphene, subsequently varying Si conductivity and influencing the transmission properties of THz waves. Simulations have demonstrated modulation depths of up to 94% at 2.5 THz in the transmission mode and 89% at 1 THz in the reflection mode. Furthermore, this study delves into a theoretical analysis and numerical simulations, exploring the modulation mechanisms, including the role of graphene’s Drude model and PN junction effects. These insights provide a robust theoretical framework for understanding the DGSA’s operation and lay a solid foundation for the design and optimization of high-performance THz modulation devices.

A comprehensive two-hybrid analysis to explore the Legionella pneumophila effector-effector interactome.

Secreted bacterial effector proteins are typically viewed as modulators of host activity, entering the host cytosol to physically interact with and modify the activity of one or more host proteins in support of infection. A growing body of evidence suggests that a subset of effectors primarily function to modify the activities of other effectors inside the host. These "effectors of effectors" or metaeffectors are often identified through experimental serendipity during the study of canonical effector function against the host. We previously performed the first global effector-wide genetic interaction screen for metaeffectors within the arsenal of Legionella pneumophila, an intracellular bacterial pathogen with over 300 effectors. Here, using a high-throughput, scalable methodology, we present the first global interaction network of physical interactions between L. pneumophila effectors. This data set serves as a complementary resource to identify and understand both the scope and nature of non-canonical effector activity within this important human pathogen.

The Particularities of the Structural Components of the Students' Educational Process, for Improving Skills in the Instructive-Tourism Practice

The content of the practice in higher education institutions assumes the position of the worker in the field of tourism, who, in addition to office work, is put in the position to go on the route, and this fact can only be achieved through an instructive-tourism practice. The subject of the research focused on the instructive-tourism practice that can have various structural components must be implemented taking into account various aspects of the tourism industry. The methods that provided us with the expected results included the analysis of the specialized literature and the structural aspects of the tourist instructive practice process. All of this presupposes the implementation of some modules for practical field activities, necessary in the training of students' professional skills. Thus, the obtained results lead us to conclude that the diversification of student practices is essential in their professional training.

IMMU-04. G-AMINOBUTYRIC ACID DRIVES GLIOBLASTOMA IN FEMALES IN AN IMMUNE-DEPENDENT MANNER

Abstract Communication with a neuronal network and accumulation of myeloid-derived suppressive cells (MDSCs) support GBM growth and therapeutic resistance. GBM incidence and outcomes differ between males and females. We previously demonstrated that granulocytic (gMDSCs) drive GBM in females. However, a lack of understanding of the host factors regulating distinct MDSC subset function remains to be a major obstacle for therapeutically targeting these cells in GBM. In this study, we identified γ-aminobutyric acid (GABA) pathway as a modulator of gMDSC activity. gMDSCs from both healthy adults and glioma patients, expressed significantly higher levels of GABA receptor B1 (GABBR1) and GABA receptor B2 (GABBR2) compared to monocytic MDSCs (mMDSCs). On contrary, GABA receptor A (GABAAR) subunits were not expressed in either MDSC subtype. Given these differences, we investigated the effect of GABA on MDSC metabolism and found an increase in L-arginine metabolism specifically in female gMDSCs following GABA treatment while no significant metabolic changes were observed in any other groups. In MDSCs, L-arginine can be metabolized via nitric oxide synthase (NOS2) or Arginase-1 (Arg-1). While treatment with GABA or the GABBR agonist baclofen increased NOS2 production in specifically in female gMDSCs, Arg-1 was not affected. Mechanistically, baclofen enhanced gMDSC-mediated T cell suppression in females. In preclinical models of GBM, baclofen treatment resulted in a truncated survival only in immunocompetent female mice, which was reversed by pharmaceutical inhibition of NOS2. Clinically, female patients on GABA analogs (pregabalin, gabapentin) had significantly lower 12-month survival probabilities compared to control population. This effect was not observed in male patients. Conversely, inhibition of GABBR with CGP35348 prolonged survival in female GBM models and reprogramed the immunosuppressive tumor microenvironment. Collectively, these results highlight that GABA alters anti-tumor immune response in a sex-specific manner. These results support the future assessment of GABA pathway inhibitors as potential immunotherapy agents in GBM.

Common and contrasting effects of 5-HTergic signaling in pyramidal cells and SOM interneurons of the mouse cortex.

Serotonin (5-hydroxytryptamine, 5-HT) is a powerful modulator of neuronal activity within the central nervous system and dysfunctions of the serotonergic system have been linked to several neuropsychiatric disorders such as major depressive disorders or schizophrenia. The anterior cingulate cortex (aCC) plays an important role in cognitive capture of stimuli and valence processing and it is densely innervated by serotonergic fibers from the nucleus raphe. In order to understand how pathophysiological 5-HT signalling can lead to neuropsychiatric diseases, it is important to understand the physiological actions of 5-HT on cortical circuits. Therefore, we combined electrophysiological recordings with pharmacology and immunocytochemistry to investigate the effects of 5-HT on Somatostatin-positive interneurons (SOM-INs) and compared these to supragranular pyramidal cells (PCs). This comparison allowed us to identify common and contrasting effects of 5-HT on SOM-INs and PCs of the aCC resulting in a specific modulation of the excitation-to-inhibition balance in PCs but not in SOM-INs.

Mitochondrial Dynamics Drive Muscle Stem Cell Progression from Quiescence to Myogenic Differentiation.

From quiescence to activation and myogenic differentiation, muscle stem cells (MuSCs) experience drastic alterations in their signaling activity and metabolism. Through balanced cycles of fission and fusion, mitochondria alter their morphology and metabolism, allowing them to affect their decisive role in modulating MuSC activity and fate decisions. This tightly regulated process contributes to MuSC regulation by mediating changes in redox signaling pathways, cell cycle progression, and cell fate decisions. In this review, we discuss the role of mitochondrial dynamics as an integral modulator of MuSC activity, fate, and maintenance. Understanding the influence of mitochondrial dynamics in MuSCs in health and disease will further the development of therapeutics that support MuSC integrity and thus may aid in restoring the regenerative capacity of skeletal muscle.

Plasmonic modulators based on enhanced interaction between graphene and localized transverse-electric plasmonic mode.

Active plasmonic modulators with high modulation depth, low energy consumption, ultra-fast speed, and small footprint are of interest and particular significance for nanophotonics and integrated optics. Here by constructing a transverse-electric (TE) plasmonic mode and maximizing the in-plane component localized on the graphene surface, we propose a high-performing plasmonic modulator based on a graphene/split ring-like plasmonic waveguide (SRPW) system with a record high modulation depth (20.46 dB/µm) and suppressed insertion loss (0.248 dB/µm) at telecom wavelength 1310 nm, simultaneously possessing pronounced advantage in broadband ability (800-1650 nm) and superior electrical performance with energy consumption of 0.43 fJ/bit and modulation speed of 200 GHz. This innovative design provides a novel approach and idea for enhancing the interaction between light and matter in the waveguide system and will certainly inspire new schemes for the development of on-chip integrated optoelectronic devices.